A brain structural connectivity biomarker for autism spectrum disorder diagnosis in early childhood

Background:Autism spectrum disorder(ASD)is associated with altered brain development,but it is unclear which specific structural changes may serve as potential diagnostic markers,particularly in young children at the age when symptoms become fully estab-lished.Furthermore,such brain markers need to meet the requirements of precision medicine and be accurate in aiding diagnosis at an individual rather than only a group level.Objective:This study aimed to identify and model brain-wide differences in structural connectivity using diffusion tensor imaging(DTI)in young ASD and typically developing(TD)children.Methods:A discovery cohort including 93 ASD and 26 TD children and two independent validation cohorts including 12 ASD and 9 TD children from three different cities in China were included.Brain-wide(294 regions)structural connectivity was measured using DTI(fractional anisotropy,FA)together with symptom severity and cognitive development.A connection matrix was constructed for each child for comparisons between ASD and TD groups.Pattern classification was performed on the discovery dataset and the resulting model was tested on the two independent validation datasets.Results:Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both autistic symptom severity and impaired general cognitive development.The majority(29/33)involved the frontal lobe and comprised five different networks with functional relevance to default mode,motor control,social recognition,language and reward.Overall,clas-sification achieved very high accuracy of 96.77%in the discovery dataset,and 91.67%and 88.89%in the two independent validation datasets.Conclusions:Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish novel individual ASD from TD children and may therefore represent a robust early brain biomarker which can address the requirements of precision medicine.

A Volumetric and Functional Connectivity MRI Study of Brain Arginine-Vasopressin Pathways in Autistic Children

Dysfunction of brain-derived arginine-vasopressin（AVP） systems may be involved in the etiology of autism spectrum disorder（ASD）. Certain regions such as the hypothalamus, amygdala, and hippocampus are known to contain either AVP neurons or terminals and may play an important role in regulating complex social behaviors.The present study was designed to investigate the concomitant changes in autistic behaviors, circulating AVP levels, and the structure and functional connectivity（FC） of speci？c brain regions in autistic children compared with typically developing children（TDC） aged from 3 to5 years. The results showed：（1） children with ASD had a signi？cantly increased volume in the left amygdala and left hippocampus, and a signi？cantly decreased volume in the bilateral hypothalamus compared to TDC, and these were positively correlated with plasma AVP level.（2） Autistic children had a negative FC between the left amygdala and the bilateral supramarginal gyri compared to TDC. The degree of the negative FC between amygdala and supramarginal gyrus was associated with a higher score on the clinical autism behavior checklist.（3） The degree of negative FC between left amygdala and left supramarginal gyrus was associated with a lowering of the circulating AVP concentration in boys with ASD.（4） Autistic children showed a higher FC between left hippocampus and right subcortical area compared to TDC.（5） The circulating AVP was negatively correlated with the visual and listening response score of the childhood autism rating scale.These results strongly suggest that changes in structure and FC in brain regions containing AVP may be involved in the etiology of autism.

Plasma Oxytocin and Arginine-Vasopressin Levels in Children with Autism Spectrum Disorder in China: Associations with Symptoms

Autism spectrum disorder（ASD） is defined by impairments of social interaction and the presence of obsessive behaviors. The ＇＇twin＇＇ nonapeptides oxytocin（OXT） and arginine-vasopressin（AVP） are known to play regulatory roles in social behaviors. However, the plasma levels and behavioral relevance of OXT and AVP in children with ASD have seldom been investigated. It is also unknown whether their mothers have abnormal plasma peptide levels. Here, using well-established methods of neuropeptide measurement and a relatively large sample size, we determined the plasma levels of the two neuropeptides in 85 normal children, 84 children with ASD, and 31 mothers from each group of children.As expected, children with ASD had lower plasma OXT levels than gender-matched controls（P = 0.028）. No such difference was found for plasma AVP concentrations. Correlation analysis showed that ASD children with higher plasma OXT concentrations tended to have less impairment of verbal communication（Rho =-0.22,P = 0.076）, while those with higher plasma AVP levels tended to have lower levels of repetitive use of objects（Rho =-0.231, P = 0.079）. Unlike the findings in children, maternal plasma OXT levels showed no group difference. However, plasma AVP levels in the mothers of ASD children tended to be lower than in the mothers of normal children（P = 0.072）. In conclusion, our results suggest that the OXT system is dysregulated in children with ASD, and that OXT and AVP levels in plasma seem to be associated with specific autistic symptoms. The plasma levels of OXT or AVP in mothers and their ASD children did not seem to change in the same direction.